MYC-Regulated Mevalonate Metabolism Maintains Brain Tumor-Initiating Cells

被引：98

作者：

Wang, Xiuxing ^{[1
]}

Huang, Zhi ^{[1
]}

Wu, Qiulian ^{[1
]}

Prager, Briana C. ^{[1
,2
]}

Mack, Stephen C. ^{[1
]}

Yang, Kailin ^{[1
,2
]}

Kim, Leo J. Y. ^{[1
]}

Gimple, Ryan C. ^{[1
,2
]}

Shi, Yu ^{[1
]}

Lai, Sisi ^{[1
]}

Xie, Qi ^{[1
]}

Miller, Tyler E. ^{[1
]}

Hubert, Christopher G. ^{[1
]}

Song, Anne ^{[1
,2
]}

Dong, Zhen ^{[1
]}

Zhou, Wenchao ^{[1
]}

Fang, Xiaoguang ^{[1
]}

Zhu, Zhe ^{[1
]}

Mahadev, Vaidehi ^{[1
]}

Bao, Shideng ^{[1
,2
]}

Rich, Jeremy N. ^{[1
,2
,3
,4
]}

机构：

[1] Cleveland Clin, Lerner Res Inst, Dept Stem Cell Biol & Regenerat Med, Cleveland, OH 44106 USA

[2] Case Western Reserve Univ, Lerner Coll Med, Cleveland Clin, Dept Mol Med, Cleveland, OH 44106 USA

[3] Univ Calif San Diego, Div Regenerat Med, Dept Med, San Diego, CA 92093 USA

[4] Univ Calif San Diego, Sch Med, Dept Med, Div Regenerat Med, San Diego, CA 92093 USA

来源：

CANCER RESEARCH | 2017年 / 77卷 / 18期

关键词：

CANCER STEM-CELLS; HMG-COA REDUCTASE; C-MYC; HUMAN GLIOBLASTOMA; GLIOMA-CELLS; PATHWAY; INHIBITION; SURVIVAL; TRIAL; DIFFERENTIATION;

D O I：

10.1158/0008-5472.CAN-17-0114

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 ;

摘要：

Metabolic dysregulation drives tumor initiation in a subset of glioblastomas harboring isocitrate dehydrogenase (IDH) mutations, but metabolic alterations in glioblastomas with wild-type IDHare poorly understood. MYCpromotes metabolic reprogramming in cancer, but targeting MYC has proven notoriously challenging. Here, we link metabolic dysregulation in patient-derived brain tumor-initiating cells (BTIC) to a nexus between MYC and mevalonate signaling, which can be inhibited by statin or 6-fluoromevalonate treatment. BTICs preferentially express meva-lonate pathway enzymes, which we find regulated by novel MYC-binding sites, validating an additional transcriptional activation role of MYC in cancer metabolism. Targeting mevalonate activity attenuated RAS-ERK-dependent BTIC growth and self-renewal. In turn, mevalonate created a positive feed-forward loop to activate MYC signaling via induction of miR-33b. Collectively, our results argue that MYC mediates its oncogenic effects in part by altering mevalonate metabolism in glioma cells, suggesting a therapeutic strategy in this setting. (C)2017 AACR.

引用

页码：4947 / 4960

页数：14

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